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Venous and arterial thrombosis in rat models: dissociation of the antithrombotic effects of glycosaminoglycans

Fucosylated chondroitin sulfate is a glycosaminoglycan from sea cucumber, made up of alternating β-d-glucuronic acid and N-acetyl-β-d-galactosamine units, like mammalian chondroitin sulfate. But the β-d-glucuronic acid residues have branches of sulfated fucose, which confer high anticoagulant and antithrombotic properties on this compound. We have now compared the anticoagulant, bleeding and antithrombotic effects of this fucosylated chondroitin sulfate and its carboxyl-reduced derivative. Both compounds have similar anticoagulant action, mostly due to acceleration of thrombin inhibition in the presence of heparin cofactor II. The native glycosaminoglycan shows a correlation among anticoagulant, bleeding and antithrombotic effects. Inhibition of thrombosis in an arterio-venous shunt occurs at low doses, which are almost ineffective in modifying the anticoagulant activity of plasma. In a venous experimental model, on the contrary, antithrombotic activity requires high doses and occurs concomitantly with an increase in the anticoagulant activity of plasma. The action of fucosylated chondroitin sulfate on thrombosis is apparently unrelated to its effect on platelet aggregation. The carboxyl-reduced derivative of fucosylated chondroitin sulfate prevented thrombosis in the arterio-venous shunt, but not in the venous experimental model. This derivative did not increase bleeding, in spite of its potent anticoagulant activity. Therefore, our results reveal a dissociation of the anticoagulant, bleeding and antithrombotic effects of the glycosaminoglycan. Furthermore, we demonstrate that a polysaccharide may be a potent inhibitor of one type of thrombotic episode, but inactive on another. We propose that the different effects of fucosylated chondroitin sulfate and its carboxyl-reduced derivative on venous thrombosis may be related to adherence of the glycosaminoglycan to the vessel wall.

Sponsorship: This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq: FNDCT, PADCT and PRONEX), Financiadora de Estudos e Projetos (FINEP) and Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ).